Nematode, insect and acarid pests destroy growing and harvested crops. In the United States, agronomic crops must compete with thousands of those pests. In addition, arthropod and helminth parasites cause hundreds of millions of dollars in economic damage to the livestock and companion animal sectors annually on a global basis. Arthropod parasites also are a nuisance to humans and can vector disease causing organisms in humans and animals.
In spite of the commercial pesticides, ectoparasiticides, endectocides and anthelmintics available today, damage to crops, livestock, companion animals and humans still occurs. Accordingly, there is ongoing research to create new and more effective pesticides, ectoparasiticides, endectocides and anthelmintics.
Certain azole derivatives which are useful as anti-ulcer agents are described in EP 405976-B1. However, that patent does not describe or suggest any pesticidal or parasiticidal utility for the azole derivatives described therein.
It is, therefore, an object of the present invention to provide a method for the control of helminth, nematode, insect and acarid pests and parasites.
It is also an object of the present invention to provide a method for the protection of growing and harvested crops from damage caused by nematode, insect and acarid attack and infestation.
It is a further object of this invention to provide a method for treating, controlling, preventing and protecting warm-blooded animals, fish and humans against infestation and infection by helminths, acarids and arthropod endo- and ectoparasites.
These and other objects of the present invention will become more apparent from the description thereof set forth below.
The present invention provides a method for the control of helminth, nematode, insect or acarid pests or parasites which comprises contacting said pests or parasites or their food supply, habitat or breeding grounds with a pesticidally or parasiticidally effective amount of a 2-(substituted thio)thiazolo[4,5-b]pyridine compound having the structural formula I 
wherein
R is halogen, nitro, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4haloalkylthio or CO2R1;
n is 0, 1, 2 or 3;
Q is C3-C6alkenyl, C3-C6haloalkenyl, C3-C7cycloalkyl, C3-C7halocycloalkyl, C4-C7cycloalkenyl, C4-C7halocycloalkenyl,
C1-C6alkyl optionally substituted with one C3-C7cycloalkyl, C3-C7halocycloalkyl or CO2R2 group,
C1-C6haloalkyl optionally substituted with one C3-C7cycloalkyl, C3-C7halocycloalkyl or CO2R2 group; and
R1 and R2 are each independently hydrogen, C1-C6alkyl, CH2(C1-C6haloalkyl), C3-C10alkenyl, C3-C10haloalkenyl, a cation,
benzyl optionally substituted on the ring with any combination of one to five halogen atoms, one or two cyano groups, one or two nitro groups, one to three C1-C4alkyl groups, one to three C1-C4haloalkyl groups, one to three C1-C4alkoxy groups or one to three C1-C4haloalkoxy groups, or
phenyl optionally substituted with any combination of one to five halogen atoms, one or two cyano groups, one or two nitro groups, one to three C1-C4alkyl groups, one to three C1-C4haloalkyl groups, one to three C1-C4alkoxy groups or one to three C1-C4haloalkoxy groups; and
the agriculturally and/or pharmaceutically acceptable salts thereof.
This invention also comprises pesticidal and parasiticidal compositions containing those compounds. Advantageously, it has been found that the 2-(substituted thio)thiazolo[4,5-b]pyridine compounds, and compositions containing them, are especially useful for the control of nematode pests.
The present invention provides a method for the control of helminth, nematode, insect or acarid pests or parasites which comprises contacting said pests or parasites or their food supply, habitat or breeding grounds with a pesticidally or parasiticidally effective amount of a 2-(substituted thio)thiazolo[4,5-b]pyridine compound of formula I.
Formula I compounds which are especially useful for the control of nematodes include
2-[(4,4,3-trifluoro-3-butenyl)thio]thiazolo[4,5-b]pyridine;
2-[(bromodifluoromethyl)thio]thiazolo[4,5-b]pyridine; and
2-[(difluoromethyl)thio]thiazolo[4,5-b]pyridine, among others.
The present invention also provides a method for the protection of growing plants from attack or infestation by nematode, insect or acarid pests which comprises applying to the foliage of the plants, or to the soil or water in which they are growing, a pesticidally effective amount of a 2-(substituted thio)thiazolo[4,5-b]pyridine compound of formula I.
The formula I compounds of this invention are useful for the control of plant parasitic nematodes and nematodes living freely in soil. Plant parasitic nematodes include, but are not limited to, ectoparasites such as Xiphinema spp., Longidorus spp. and Trichodorus spp.; semi-parasites such as Tylenchulus spp.; migratory endoparasites such as Pratylenchus spp., Radopholus spp. and Scutellonema spp.; sedentary parasites such as Heterodera spp., Globodera spp. and Meloidogyne spp.; and stem and leaf endoparasites such as Ditylenchus spp., Aphelenchoides spp. and Hirshmaniella spp.
The 2-(substituted thio)thiazolo[4,5-b]pyridine compounds of formula I are also useful for controlling insect and/or acarid pests. Insects controlled by the formula I compounds of this invention include, but are not limited to, Lepidoptera such as tobacco budworms, cabbage loopers, cotton boll worms, beet armyworms, southern armyworms and diamondback moths; Homoptera such as aphids, leaf hoppers, plant hoppers and white flies; Thysanoptera such as thrips; Coleoptera such as boll weevils, Colorado potato beetles, southern corn rootworms, western corn rootworms and mustard beetles; and Orthoptera such as locusts, crickets, grasshoppers and cockroaches. Acarina controlled by the formula I compounds of this invention include, but are not limited to, mites such as two-spotted spider mites, carmine spider mites, banks grass mites, strawberry mites, citrus rust mites and leprosis mites.
In practice generally about 0.1 ppm to about 10,000 ppm and preferably about 1 ppm to about 5,000 ppm of a formula I compound, dispersed in water or another liquid carrier, is effective when applied to plants or the soil or water in which the plants are growing or are to be grown to protect the plants from nematode, insect and/or acarid attack and infestation.
The 2-(substituted thio)thiazolo[4,5-b]pyridine compounds are also effective for controlling nematode, insect and/or acarid pests when applied to the foliage of plants and/or to the soil or water in which said plants are growing or are to be grown in sufficient amount to provide a rate of about 0.1 kg/ha to 4.0 kg/ha of active ingredient.
While the formula I compounds of this invention are effective for controlling nematode, insect and/or acarid pests of agronomic crops, both growing and harvested, when employed alone, they may also be used in combination with other biological agents used in agriculture, including, but no limited to, other nematicides, insecticides and/or acaricides. For example, the formula I compounds of this invention may be used effectively in conjunction or combination with pyrethroids, phosphates, carbamates, cyclodienes, endotoxin of Bacillus thuringiensis (Bt), formamidines, phenol tin compounds, chlorinated hydrocarbons, benzoylphenyl ureas, pyrroles and the like.
The compounds of this invention may be formulated as emulsifiable concentrates, flowable concentrates or wettable powders which are diluted with water or other suitable polar solvent, generally in situ, and then applied as a dilute spray. Said compounds may also be formulated in dry compacted granules, granular formulations, dusts, dust concentrates, suspension concentrates, microemulsions and the like all of which lend themselves to seed, soil, water and/or foliage applications to provide the requisite plant protection. Such formulations or compositions of the present invention include a formula I compound of this invention (or combinations thereof) admixed with one or more agronomically acceptable inert, solid or liquid carriers. Those compositions contain a pesticidally effective amount of said compound or compounds, which amount may vary depending upon the particular compound, target pest, and method of use. Those skilled in the art can readily determine what is a pesticidally effective amount without undue experimentation.
This invention also provides a method for treating, controlling, preventing and protecting warm-blooded animals, including humans, and fish against infestation and infection by helminths, acarids and arthropod endo- and ectoparasites which comprises orally, topically or parenterally administering or applying to said animals an anthelmintically, acaricidally or endo- or ectoparasiticidally effective amount of a 2-(substituted thio)thiazolo[4,5-b]pyridine compound of formula I.
The above method is particularly useful for controlling and preventing helminth, acarid and arthropod endo- and ectoparasitic infestations and infections in warm-blooded animals such as cattle, sheep, swine, camels, deer, horses, poultry, fish, rabbits, goats, dogs and cats as well as humans.
Helminthias is a widespread disease found in many farm and companion animals and is responsible for significant economic losses throughout the world. Among the helminths causing significant damage are members of the class Trematoda, commonly known as flukes or flatworms, especially members of the genera Fasciola, Fascioloides, Paramphistomum, Dicrocoelium, Eurytrema, Ophisthorchis, Fasciolopsis, Echinostoma and Paragonimus. Helminthiases is also caused by a group of worms referred to as nematodes. Nematodes cause serious damage to the walls and tissues of the organs in which they reside, including the intestinal tract, heart, lungs and blood vessels, and are a primary cause of anemia. If left untreated they may result in death to the infected animals. The nematodes most commonly found to be the infecting agents of warm-blooded animals include members of the genera Haemonchus, Ostertagia, Cooperia, Oesphagastomum, Nematodirus, Dictyocaulus, Trichuris, Dirofilaria, Ancyclostoma, Ascaris and the like. Advantageously, the formula I compounds of this invention are useful against the causative agents of helminthiases.
Besides controlling helminths, the formula I compounds of this invention control endoparasitic arthropod infestations such as cattle grub and stomach bot. In addition, acarid and arthropod ectoparasitic infestations in warm-blooded animals and fish including, but not limited to, lice, mites, ticks, nasal bots, keds, biting flies, muscoid flies, flies, myiasitic fly larvae, chiggers, gnats, mosquitoes and fleas may be controlled, prevented or eliminated by the 2-(substituted thio)thiazolo[4,5-b]pyridine compounds of this invention. The formula I compounds of this invention may also be used to control mites which are parasitic on warm-blooded mammals and poultry including mites of the orders Acariformes and Parasitiformes. Arthropod ectoparasites which may be controlled by the formula I compounds of this invention include, but are not limited to, biting lice, sucking lice, bot flies, biting flies, gnats, mosquitoes and fleas. Biting lice include members of Mallophaga such as Bovicola bovis, Trichodectes canis and Damilina ovis. Sucking lice include members of Anoplura such as Haematopinus eurysternus, Haematopinus suis, Linognathus vituli and Solenopotes capillatus. Biting flies include members of Haematobia.
For oral administration to warm-blooded animals, the formula I compounds may be formulated as animal feeds, animal feed premixes, animal feed concentrates, pills, solutions, pastes, suspensions, drenches, gels, tablets, boluses and capsules. In addition, the formula I compounds may be administered to the animals in their drinking water. For oral administration, the dosage form chosen should provide the animal with about 0.01 mg/kg to 100 mg/kg of animal body weight per day of the formula I compound.
Alternatively, the formula I compounds may be administered to animals parenterally, for example, by intraruminal, intramuscular, intravenous or subcutaneous injection. The formula I compounds may be dispersed or dissolved in a physiologically acceptable carrier for subcutaneous injection. Alternatively, the formula I compounds may be formulated into an implant for subcutaneous administration. In addition the formula I compound may be transdermally administered to animals. For parenteral administration, the dosage form chosen should provide the animal with about 0.01 mg/kg to 100 mg/kg of animal body weight per day of the formula I compound.
The formula I compounds may also be applied topically to the animals in the form of dips, dusts, powders, collars, medallions, sprays and pour-on formulations. For topical application, dips and sprays usually contain about 0.5 ppm to 5,000 ppm and preferably about 1 ppm to 3,000 ppm of the formula I compound. In addition, the formula I compounds may be formulated as ear tags for animals, particularly quadrupeds such as cattle and sheep.
The formula I compounds of this invention may also be used in combination or conjunction with one or more other parasiticidal compounds including, but not limited to, anthelmintics, such as benzimidazoles, piperazine, levamisole, pyrantel, praziquantel and the like; endectocides such as avermectins, milbemycins and the like; ectoparasiticides such as arylpyrroles, organophosphates, carbamates, gamabutyric acid inhibitors including fipronil, pyrethroids, spinosads, imidacloprid and the like; insect growth regulators such as pyriproxyfen, cyromazine and the like; and chitin synthase inhibitors such as benzoylureas including flufenoxuron.
The formula I compounds may also be used in combination or conjunction with one or more conventional synergists such as piperonyl butoxide, N-octyl bicycloheptene dicarboximide, dipropyl pyridine-2,5-dicarboxylate and 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde to enhance efficacy, broaden spectrum and provide a convenient method for parasite control.
The parasiticidal compositions of the present invention include a formula I compound of this invention (or combinations thereof) admixed with one or more pharmaceutically and/or agronomically acceptable inert, solid or liquid carriers. Those compositions contain a parasiticidally effective amount of said compound or compounds. Those skilled in the art can readily determine what is a parasiticidally effective amount without undue experimentation.
The present invention also provides novel 2-(substituted thio)thiazolo[4,5-b]pyridine compounds having the structural formula Ia 
wherein
R is halogen, nitro, cyano, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, C1-C4alkylthio, C1-C4haloalkylthio or CO2R1;
n is 0, 1, 2 or 3;
Q is C3-C6haloalkenyl, C3-C7cycloalkyl, C3-C7halocycloalkyl, C4-C7cycloalkenyl, C4-C7halocycloalkenyl,
C1-C6alkyl substituted with one C3-C7cycloalkyl or C3-C7halocycloalkyl group, or
C1-C6haloalkyl optionally substituted with one C3-C7cycloalkyl or C3-C7halocycloalkyl group,
provided that Q is other than CF2H; and
R1 is hydrogen, C1-C6alkyl, CH2(C1-C6haloalkyl), C3-C10alkenyl, C3-C10haloalkenyl, a cation,
benzyl optionally substituted on the ring with any combination of one to five halogen atoms, one or two cyano groups, one or two nitro groups, one to three C1-C4alkyl groups, one to three C1-C4haloalkyl groups, one to three C1-C4alkoxy groups or one to three C1-C4haloalkoxy groups, or
phenyl optionally substituted with any combination of one to five halogen atoms, one or two cyano groups, one or two nitro groups, one to three C1-C4alkyl groups, one to three C1-C4haloalkyl groups, one to three C1-C4alkoxy groups or one to three C1-C4haloalkoxy groups; and
the agriculturally and/or pharmaceutically acceptable salts thereof.
In addition, the present invention provides 2[(difluoromethyl)thio]thiazolo[4,5-b]pyridine.
Exemplary of halogen hereinabove are fluorine, chlorine, bromine and iodine. The terms xe2x80x9cC1-C4haloalkylxe2x80x9d, xe2x80x9cC1-C6haloalkyl, xe2x80x9cC1-C4haloalkoxyxe2x80x9d, xe2x80x9cC1-C4haloalkylthioxe2x80x9d, xe2x80x9cC3-C7halocycloalkylxe2x80x9d, xe2x80x9cC3-C6haloalkenylxe2x80x9d, xe2x80x9cC3-C10haloalkenylxe2x80x9d and xe2x80x9cC4-C7halocycloalkenylxe2x80x9d are defined as a C1-C4alkyl group, a C1-C6alkyl group, a C1-C4alkoxy group, a C1-C4alkylthio group, a C3-C7cycloalkyl group, a C3-C6alkenyl group, a C3-C10alkenyl group and a C4-C7cycloalkenyl group substituted with one or more halogen atoms, respectively. As used in formulas I and Ia above, cation designates alkali metals, alkaline earth metals, manganese, copper, iron, zinc, cobalt, lead, silver, nickel, ammonium or organic ammonium. Alkali metals include sodium, potassium and lithium. Alkaline earth metals include calcium and magnesium. Organic ammonium cations include, but are not limited to, monoalkylammonium, dialkylammonium, trialkylammonium, tetraalkylammonium, monoalkenylammonium, dialkenylammonium, trialkenylammonium, monoalkynylammonium, dialkynylammonium, monoalkanolammonium, dialkanolammonium, C5-C6cycloalkylammonium, piperidinium, morpholinium, pyrrolidinium, benzylammonium and the like.
The formula I compounds of this invention may be prepared by reacting a 2-thiolthiazolo[4,5-b]pyridine compound having the structural formula II with an electrophile compound having the structural formula III and a base in the presence of a solvent as shown below in Flow Diagram I. 
In addition, certain compounds of formula I may be converted into other compounds of formula I by using conventional procedures known to those skilled in the art.
Starting compounds of formula II are known in the art and may be prepared by the procedures described by K. Smith et al in Sulfur Letters, 18(2), pages 79-95 (1995).
In order to facilitate a further understanding of the invention, the following examples are presented to illustrate more specific details thereof. The invention is not to be limited thereby except as defined in the claims.